Parkinson's disease is a progressive neurodegenerative disorder affecting the elderly, characterized by neurodegeneration of nigrostriatal domain neurons. Studies in our laboratory have been focused on identifying factors that are important for the survival and plasticity of dopamine neurons, which could protect them from degeneration or that are important for the survival and plasticity of dopamine neurons, which could protect them from degeneration or enhance compensatory responses. In response to MPTP induced toxicity, midbrain dopaminergic neurons exhibit some regenerative capacity, for young animals treated with the toxin are able to spontaneously recover. However, in the process of normal aging, this regenerative capacity of dopaminergic neurons becomes greatly reduced. We observed in response to MPTP induced degeneration of substantia nigra dopamine neurons in young mice, that there is a robust induction of IL-1 alpha which lasts for nearly two weeks and is associated with collateral sprouting of the ventral tegmental dopamine neurons. In contrast, to middle-aged mice we detected neither an induction of IL-1 alpha or collateral sprouting. To determine whether this induction of IL-1 alpha is necessary for lesion-induced sprouting to occur we are proposing to perform further experiments in mice in which the high affinity IL-1 alpha receptor has been genetically ablated. In further studies we obtained evidence that there may be changes in the extracellular matrix in middle-aged mice that may also contribute to reduced plasticity. Thus, we propose further studies to determine whether ectopic expression of IL-1, by retroviral infection of progenitor cells in middle-aged mice, can stimulate compensatory sprouting of dopamine neurons. In addition, to directly address whether the extracellular environment is play a role in reducing the ability of dopaminergic neurons to collateral sprout, we are proposing to graft fetal dopaminergic neurons into young and middle aged mice and compare the extent of fiber outgrowth. In specific regions of the CNS, neurons die and are being continuously replaced with newly developed neurons. It has recently become appreciated that neural stem cells are more widely dispersed than previously thought and can be induced to proliferate in response to brain injury. We have preliminary data showing that in response to MPTP, newly proliferated cells can be found in the substantia nigra which can have an un-committed phenotype. After longer periods of time after labeling our data suggests the possibility that these cells may eventually differentiate into dopamine neurons. Thus, we propose to establish whether new dopamine neurons are produced in response to injury or can be stimulated to differentiate by ectopically expressing cytokines, which are able to regulate neuronal.